1. Technical Field of the Invention
This invention is related to the biomedicine field, particularly with respect to cell implants for the production of biological factors in the treatment of chronic degenerative diseases, such as the generation of material for tissue implants like splints.
2. Background of the Invention
The deficiency of a biological factor in an individual is the main cause of the appearance of chronic degenerative diseases like diabetes mellitus, Parkinson""s disease, hypothyroidism and others.
The traditional treatments of some of these diseases have consisted in the application of deficient biological factors in individuals or substances that stimulate their production, generally by means of injections of products obtained from chemistry or biotechnology. This type of treatment has several disadvantages, particularly in relation to the frequency of doses required to maintain the factor at an optimal level, which is virtually impossible to achieve. This, however, continues to be the method that is most frequently used, as it is the easiest and cheapest option available.
In order to improve the bioavailability of the factor, attempts have been made to develop methods, devices and apparatus to control its release.
One alternative refers to pumps that control the dosage of the biological factor, in accordance with its requirement or demand. Apart from being complicated, this method has proved unable to control the dosage as there are no means to measure demand with a certain degree of accuracy and the pumps therefore have not been successful.
Another alternative that has been tried is the implant of cells that produce the biological factor. However, the direct contact of the cells with the patient""s body prevents the flow of nutrients with the consequent destruction of cells and so the life of the implanted cells is relatively short and transfer of the biological factors is limited. Consequently, their therapeutic effect is deficient.
The tissues that appear to reject the implants are made up of cells called lymphocytes, plasmatic cells and antibodies. Fibrocollagen is the means to cover foreign bodies, even when they are positive. The amount of fibrocollagen produced is relatively high and it is therefore able to destroy the implanted cells.
These tissues, that are formed in a natural way, could be used in turn as splints for implants in different parts of the body such as blood vessels, urethra, etc, since it is recommendable that said splints come from the patient""s own tissues. However, a limiting factor has been found: in order for them to be effective, greater availability in the amount and size of the tissues is required than is available in the body and to date there has not been any method to obtain this type of useful material for use as a splint.
In order to try to avoid the problems of rejection derived from direct cell implant, a variety of devices has been designed that generally consist of a chamber or capsule where cells are placed in such a way that they are isolated and have no contact with the individual""s immune system.
The implant devices that contain the cells are generally composed of natural polymers like collagen and alginates or synthetic polymers such as polyacrylates, vinyl-acrylonitrile, and poly-xylene.
In U.S. Pat. No. 5,614,205, for example, a matrix is described consisting of a poly-para-xylene membrane and a cell culture that produces insulin for the treatment of diabetes mellitus. The membrane has a certain porosity that permits the passage of nutrients and biological factors, but prevents the passage of immune agents. It is mentioned that the biocompatible material does not produce rejection.
In the U.S. Pat. No. 5,569,462 a description is given of how the mortality of cells producing the biological factor of interest occurs because the flows of nutrients and waste products are not adequate during the ischemic period of the implant. The alternative proposal consists in using a device with a chamber for cells where said chamber is immuno-isolated with biocompatible material such as polytetrafluorethylene (PTFE) 15 microns in width and a porosity 5 microns.
Additionally, the uses of immunomodulatory agents such as immuno-suppressive agents like mycophenolic acid, cyclosporin, rapamacyn, etc. or anti-inflammatory agents like corticosteroids are required.
Given that the ischemic period finishes when good neovascularization has been achieved, the inventors propose the use of means for a better neovascularization, such as the use of a substance or cells that promote or produce the substance stimulating neovascularization.
These devices do not satisfactorily solve the various disadvantages of the implants already mentioned because, although they are biocompatible materials, there is still tissue formation and inadequate vascularization around the device in relatively short periods of time after the implant. Hence the flow of blood to the tissues in that region is low and therefore nutrient availability is also low.
Although they are permeable, the device construction materials represent an additional barrier to the exchange of nutrients and biological factors between the implanted cells and the patient""s body.
Furthermore, it is well known that the use of products like cyclosporin to reduce the immune response and inhibit the recognition and rejection of transplants and/or implants has negative effects on neovascularization, and therefore the probability is increased of the transplant or implant being unsuccessful.
The U.S. Pat. No. 5,725,854 claims a method for the treatment of diseases that comprises the administration of Sertolli cells, together with cells that produce the biological factor. Here an attempt is made to create an immunologically privileged site. It is well known that Sertolli cells promote immunological tolerance and contain a high amount of elements to protect the cells that produce the biological factor and to maintain their functioning for an indefinite period of time. However, with this alternative rejection is not completely eradicated and it is therefore necessary to continue administering immunosuppressive or immunomodulatory agents which, in turn, have a negative effect on neovascularization.
Furthermore, in none of the previously mentioned inventions is a way established to control the amount of fibrocollagen produced, and it is precisely this substance that is the main factor behind implant rejection.
For this reason, it is still necessary to find an efficacious, efficient way of successfully implanting cells producing biological factors for the treatment of disease.
It is therefore one of the objectives of this invention to provide a procedure for the development of tissues in a conveniently easy and inexpensive way that can be used both to receive the implant of cells producing biological factors for the treatment of diseases and to provide splints that can be used as tissue grafts.
A further objective of this invention is to have the means to form natural fibrocollagen tubes of a controlled width, diameter and length.
Another of the objectives of this invention is to provide an isolated site with characteristics that will permit good neovascularization for the adequate transfer of nutrients and biological factors.
Yet another objective of this invention is to reduce the use of immunomodulatory substances.
These and other objectives will be appreciated in greater detail in the following detailed description of the invention.